ESC 2016 - Rome

A rapid and effective antidote for anticoagulant bleeds

Background

Andexanet alfa is an antidotum specially developed to reverse the anticoagualant activity of factor Xa inhibitors, for instance in case of bleedings. It has been shown in healthy volunteers that andexanet can reverse anti-factor Xa activity, but to date the effect in patients with severe bleedings is not known.
The effect of andexanet in patients with acute bleedings has been studies in the ‘andexanet alfa, a novel antidote to the anticoagulation effects of fxa inhibitors’ (ANNEXA-4) study. Interim results of this study included 67 patients with a mean age of 77 years, who needed an antidotum urgently to stop acute major bleedings, within 18 hours after having received direct (apixaban, rivoroxaban, edoxaban) or indirect (enoxaparine) factor Xa inihibtors.
Due to ethical reasons, the study was not randomised, instead all patients received andexanet: first a bolus (15-30 min), then 2 hours of infusion. Dosing of andexanet was based on the timing and dose of the factor Xa inhibitor the patient had received. 69 patients were included in the safety analysis and 47 in the efficacy analysis. Excluding patients in the efficacy analysis was based on low factor Xa activity.

Main results

The most prevalent locations of bleedings were gastrointestinal (˜51%) and intracranial (˜42%).

At the end of the andexanet bolus, anti-factor Xa activity was reduced by 89% (95%CI: -58 tot --94%) in patients on rivaroxaban (n=26). At the end of the infusion it had lowered by 86% (95%CI: -55 tot -93%).

In patients on apixaban (n=20), a decrease of anti-factor Xa activity of 93% was seen between baseline and end of bolus.

After 12 hours anti-factor Xa activity was 64% lower as compared with baseline, and haemostatic efficacy was good to excellent in 79% of patients, predominantly in patients with gastrointestinal bleedings.

Anticoagulant therapy was restarted within 30 days in 18 patients (27%).

Thrombotic events occurred in 12 patients (18%) within 30 days after andexanet treatment.

10 patients (15%) died, of whom 6 due to a cardiovascular cause.

Conclusion

A bolus of andexanet alfa plus 2 hours of infusion rapidly reversed anti-factor Xa acitivity. This resulted in effective haemostatis in most patients. Thrombotic events occurred, with the numbers being consistent with the high-risk profile of the patients. Stuart Connolly noted during the press conference that this observation is not surprising, because patients no longer received anticoagulants, which were often not restarted. In answer to the question whether this was related to ‘tissue factor pathway inhibitor (TFPI), Connolly answered that interaction with this protein occurs, but that he believes that the observed thrombotic events were not a result thereof. Rather, that they may be the consequence of underlying disease and discontinuing anticoagulation.

This study reflects a non-prespecified interim analysis. No statistical penalty has been applied, because it had been decided a priori that, no matter what the interim analysis would yield, the study would continue, until the moment that the calculated inclusion criteria with regard to power would be met. The interim analysis was performed because of the upcoming potential approval by the FDA (for the moment, no approval has been granted), to inform the public.

Our reporting is based on the information provided during the ESC congress –